The USC Consortium, one of the Colon CFR centers, is comprised of a high risk clinic at the Cleveland Clinic and six population-based centers: University of Arizona, University of Colorado, Dartmouth, University of Minnesota, University of North Carolina, and USC. The Colon CFR is dedicated to the maintenance of a comprehensive infrastructure to facilitate collaborative, interdisciplinary studies regarding the etiology, prevention, and clinical management of colorectal cancer (CRC). The current RFA (CA-08-502) is a U24, which is intended to maintain and enhance the core infrastructures of the Colon CFR. In accordance with this mechanism, we have the following specific aims for Phase III. 1) Expand families already in the Colon CFR who carry a deleterious mutation in a mismatch repair (MMR) gene (MLH1, MSH2, or MSH6), which will enable more informative analyses of penetrance and risk factors among carriers. There are 38 such families in the USC Consortium;2) Recruit through the Cleveland Clinic (CCF) 97 additional families who either carry an MMR or MYH mutation or meet Amsterdam I or II criteria. 3) Follow current families with passive and active follow-up every five years to obtain updates on family history of cancer and vital status, pathology reports and tumor blocks on any new CRC cases and HNPCC-related cancers, and informed consents for possible future studies of clinical data. There are 3,709 population-based and 404 clinic-based subjects eligible for follow-up in the USC Consortium as of 11/07;4) Obtain information on stage for all probands for whom it is not already available and obtain an informed consent to obtain copies of selected medical records from all probands to facilitate future clinical studies. At the USC Consortium, we will obtain this information for 1,443 probands;5) Collaborate with the Molecular Characterization Core by dispatching required biospecimens to the Mayo Clinic for immunohistochemistry (IHC) testing of the MLH1, MSH2, and MSH6 proteins, and MMR mutation testing guided by the IHC results, and to the Queensland Institute of Medical Research for testing for somatic mutations in BRAF. MLH1 methylation testing for the Colon CFR will continue in the laboratory of Dr. Peter Laird at USC;6) maintain the biospecimens core, add to the core all new samples from subjects recruited in Phase III, and coordinate future efforts with the Central Repository. In the USC Consortium, to date from Phases I and II combined, we have blood samples from 3,635 subjects and tumor blocks from 1,390 cases;7) maintain the local bioinformatics core and coordinate efforts with RTI. 8) Maintain the administrative core. We can accomplish these proposed aims within the current budget defined in the RFA and doing so will enhance and maintain the core elements of the Colon CFR infrastructure, which is proving to be an outstanding resource for studies of colorectal cancer causes and prevention.